The term diabetes mellitus (DM) (ICD/10 codes E10-E14) describes several syndromes of abnormal carbohydrate metabolism that are characterized by hyperglycemia. It is associated with a relative or absolute impairment in insulin secretion, along with varying degrees of peripheral resistance to the action of insulin. According to the new etiologic classification of DM, four categories are differentiated: type 1 diabetes (T1D), type 2 diabetes (T2D), other specific types, and gestational diabetes mellitus (American Diabates Association (ADA), 2003). T2D, accounting for 90% of all diabetes mellitus cases worldwide, is characterized by adult onset insulin resistance and a rise in blood sugar concentration.
The causes of T2D are multi-factorial and include both genetic and environmental elements that affect beta cell function and tissue insulin sensitivity (muscle, liver, adipose tissue, pancreas). Although there is considerable debate as to the relative contributions of beta-cell dysfunction and reduced insulin sensitivity to the pathogenesis of diabetes, it is generally agreed that both of these factors play important roles (Scheen A J, 2003). Both impaired insulin secretion and insulin action cause the development of type 2 diabetes. Insulin resistance is an early feature in the pathophysiology of type 2 diabetes.
T2D is a heterogeneous disease resulting from the interaction of environmental factors such as obesity or sedentary lifestyle, with variety of diabetogenic genes (Stumvoll et al 2005). Abnormal glucose homeostasis occurs when either insulin sensitivity or insulin secretion or both are altered (Bajaj M and Defronzo R A, 2003, Weyer C et al, 1999). An early finding in this development is insulin resistance, defined as impaired insulin-mediated glucose clearance in insulin-sensitive tissues (skeletal muscle, liver and adipose tissue) (Warram J H et al, 1990). Elevation of glucose levels triggers β-cells to produce and secrete more insulin, which compensates for the disturbance in glucose homeostasis (Bajaj M and Defronzo R A, 2003). The duration of hyperglycemia-hyperinsulinemia state depends on insulin secretory capacity, mass and apoptosis rate of β-cells (Porte D, Jr. and Kahn S E, 2001). Furthermore, β-cells can loose their insulin secretion capacity because of glucose toxicity or other reasons (Kaiser N et al, 2003). When β-cells fail to compensate for insulin resistance blood glucose concentration increases. Thus, over time subclinical hyperglycemia tends to progress to impaired glucose tolerance (IGT) and further to type 2 diabetes. However, only 20-50% individuals with primary insulin resistance and IGT develop type 2 diabetes in 10 years (Alberti K G, 1998). Therefore, these individuals have almost undetectable β-cell dysfunction early in the course of the disease. On the other hand, lifestyle intervention and/or administration of insulin-sensitizing drugs may alleviate insulin resistance and prevent or even reverse the progression from IGT to type 2 diabetes (Tuomilehto J et al, 2001).
No major single gene explaining the development of T2D has been identified although more than 30 GWS studies have been performed and more than a hundred candidate genes have been evaluated for T2D. The T2D association of only a handful of T2D candidate genes has been replicated in multiple studies. The association of TCF7L2 and PPARG with T2D is widely reproduced (Deeb SS et al, 1998; Hara K et al, 2000; Altshulert D et al, 2000; Mori H et al, 2001, Grant S F at al, 2006, Saxena R et al, 2006), and that of KCNJ11 (Hani E H et al, 1998; Gloyn A L et al, 2001; Gloyn A L et al, 2003), CAPN10 (Tsuchiya T et al, 2006) and PPARGC1A (Barosso I et al, 2006) have now been replicated by multiple groups.
In 2000, there were approximately 171 million people, worldwide, with diabetes. The number of people with diabetes will expectedly more than double over the next 25 years, to reach a total of 366 million by 2030 (WHO/IDF, 2004). The two main contributors to the worldwide increase in prevalence of diabetes are population ageing and urbanization, especially in developing countries, with the consequent increase in the prevalence of obesity (WHO/IDF, 2004). Currently more than 1 billion adults are overweight—and at least 300 million of them are clinically obese. This suggests the role of relatively modem environmental or behavioral risk factors such as high caloric intake or sedentary lifestyle. However, ethnic differences in the incidence and prevalence of T2D and the enrichment of T2D in families suggest heritable risk factors to play a major role. In the USA, there are over 15 million diabetics and 15 million people with impaired glucose tolerance. Almost one million Americans become diabetic annually.
The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of various organs, especially the eyes, kidneys, nerves, heart, and blood vessels (ADA, 2003). In 2000, 3.2 million people died from complications associated with diabetes. Diabetes has become one of the major causes of premature illness and death in most countries, mainly through the increased risk of cardiovascular disease (CVD). Diabetes is a leading cause of blindness, amputation and kidney failure. These complications account for much of the social and financial burden of diabetes (WHO/IDF, 2004).
Because of the chronic nature of T2D, the severity of its complications and the means required to control them, diabetes is a costly disease, not only for the affected individual and his/her family, but also for the health authorities. In the US direct medical and indirect expenditures attributable to diabetes in 2002 were estimated at $132 billion. Direct medical expenditures alone totalled $91.8 billion and comprised $23.2 billion for diabetes care, $24.6 billion for chronic complications attributable to diabetes, and $44.1 billion for excess prevalence of general medical conditions. Attributable indirect expenditures resulting from lost workdays, restricted activity days, mortality, and permanent disability due to diabetes totalled $39.8 billion (ADA, 2003).
Obesity is an excessive accumulation of energy in the form of body fat which impairs health. As the direct measurement of body fat is difficult, Body Mass Index (BMI), a simple ratio of weight to the square of height (kg/m2), is typically used to classify overweight and obese adults. Consistent with this, the WHO has published international standards for classifying overweight and obesity in adults. There are several causes of obesity as obesity is a complex, multi-factorial chronic disease involving environmental (social and cultural), genetic, physiologic, metabolic, behavioral and psychological components. For example nearly 200 cases of obesity associated with a single gene mutation has been reported (Mutch and Clement, 2006). Twin studies have suggested a heritability of fat mass of between 40% and 70% with a concordance of 0.7-0.9 between monozygotic twins compared to 0.35-0.45 between dizygotic twins (Stunkard et al. 1986)
Although obesity is not a recent phenomenon as the historical roots of obesity can be traced back to 25,000 years ago, the epidemic of obesity is a global health issue across all age groups, especially in industrialized countries (American Obesity Association, 2006). According to WHO's estimate there are more than 300 million obese people (BMI>30) world-wide. Today, for example almost 65% of adult Americans (about 127 million) are categorized as being overweight or obese. There is also evidence that obesity is increasing problem among children, for example in the USA, the percentage of overweight children (aged 5-14 years) has doubled in the last 30 years, from 15% to 32%. The degree of health impairment of obesity is determined by three factors: 1) the amount of fat 2) the distribution of fat and 3) the presence of other risk factors. It is the second leading cause of preventable death in the U.S. Obesity affects all major bodily systems—heart, lung, muscle and bones—and is considered as a major risk factor for several chronic disease conditions, including coronary heart disease (CHD), type 2 diabetes mellitus (T2D), hypertension, stroke, and cancers of the breast, endometrium, prostate and colon (Burton & Foster 1985).
The economic cost attributable to obesity is substantial and is close to $100 billion/yr (Wolf & Colditz 1998). Obesity accounts for 2-6% of total health care costs in several developed countries; some estimates put the figure as high as 7%. The true costs are undoubtedly much greater as not all obesity-related conditions are included in the calculations.
The high prevalence of type 2 diabetes and T2D related conditions such as obesity and increasing population affected shows unmet medical need both for diagnostic methods to identify subjects having increased risk for T2D or a T2D related condition and for better therapies to prevent and to treat T2D and various T2D related conditions. The present invention provides a number of new correlations between various polymorphic alleles and T2D and/or obesity. The T2D and/or obesity associated polymorphic alleles, genes and loci disclosed in this invention provide the basis for improved risk assessment, diagnosis and prognosis of T2D or a T2D related condition, and for the development of novel therapies to prevent and treat T2D or a T2D related condition.